Abstract

The ability to model human brain development in vitro represents an important step in our study of developmental processes and neurological disorders. Protocols that utilize human embryonic and induced pluripotent stem cells can now generate organoids which faithfully recapitulate, on a cell-biological and gene expression level, the early period of human embryonic and fetal brain development. In combination with novel gene editing tools, such as CRISPR, these methods represent an unprecedented model system in the field of mammalian neural development. In this review, we focus on the similarities of current organoid methods to in vivo brain development, discuss their limitations and potential improvements, and explore the future venues of brain organoid research.

Comparison of in vivo and in vitro brain development. A simplified representation of the cell biological complexity of the in vivo developing brain and the in vitro brain organoid. The early stages (left) possess a similar morphological level of complexity. Later stages (right) differ in the size of the cortical wall and diversity and complexity of neural progenitor populations. Note the absence of vasculature (orange) in the organoid, a reduced SVZ and the rudimentary organization of the neuronal layers. VZ – ventricular zone, SVZ – subventricular zone, CP – cortical plate.

Timeline of human brain development. A timeline showing relative similarities between human in vivo brain development and the brain organoid protocol timeline. The relative similarity (cyan-purple gradient) is based on cell-biological and transcriptomics data from several studies and is not a quantitative measure. Human developing brain and brain organoids are not to scale. Abbreviations: pcw – post-conception weeks.

Brain organoids as a tool to study neurodevelopmental disorders. (A) . used brain organoids to study brain development in a microcephalic patient with a mutation in CDK5RAP2 gene, which causes microcephaly. Organoids produced from the patient were smaller than the control, and had a change in the cleavage plane orientation of the APs, which might contribute to the decreased progenitor pool, and thus to the smaller brain size. (B) . used brain organoids to study idiopathic autism. Organoids generated from patients showed an increase in GABAergic inhibitory neurons (depicted in green), as compared to the healthy relatives.

Potential future brain modeling capabilities. A simplified schematic representing human brain development timescale, indicating several milestones during embryonic development (green), which could be modeling in brain ogranoids in future, following certain technical improvements (dark purple, for details, please see main text) (for a more detailed timescale of milestones, please see ()). The timescale also indicates the onset of a subset of neurodevelopmental and neurological diseases, which could be modeled (or partly already are) by using the brain organoid technique (petrol color).

Personalized medicine using brain organoids. Brain organoids in the future might be used in a personalized medicine approach. Individual-derived cells (obtained as a part of a preventive monitoring or disease diagnostics) or cells derived from the embryo as a part of prenatal diagnostics can be reprogrammed into iPS cells, and brain organoids on a large scale could be generated. This large number of organoids could be used for genetic screens and drug screening. Genome editing could also be performed to test the outcome on the brain phenotype. With this in mind, personalized therapeutic strategies may be designed.